1. Field of the Invention
The present invention relates to methods for making therapeutics tailored to individual patients or sub-populations of patients, as well as methods of using such therapeutics to treat malignancies, pathogenic infections, and other conditions, and to reduce or prevent transplant rejection.
2. Description of the Related Art
Many malignant cells display epitopes that are specific not only to the type of malignancy but also to the individual patient. In some aspects, the present invention is directed to therapeutics that can be targeted to patient-specific epitopes, such as those displayed on malignant lymphocytes.
Lymphocytes are critical to the immune system of vertebrates. Lymphocytes are produced in the thymus, spleen and bone marrow (adult) and represent about 30% of the total white blood cells present in the circulatory system of humans (adult). There are two major sub-populations of lymphocytes: T cells and B cells. T cells are responsible for cell-mediated immunity, while B cells are responsible for antibody production (humoral immunity). In a typical immune response, T cells are activated when the T cell receptor binds to fragments of an antigen that are bound to major histocompatibility complex (“MHC”) glycoproteins on the surface of an antigen presenting cell; such activation causes release of biological mediators (“interleukins”) which, in essence, stimulate B cells to differentiate and produce antibody (“immunoglobulins”) against the antigen.
The etiology of hematological cancers such as lymphomas, leukemias and multiple myelomas varies or is unknown. Suspected causes range from viral and chemical exposure to familial propensities. A common denominator in these cancers however, is that they all begin with a malignantly transformed B-cell or T-cell which divides to form a clone of cells that express the same Fab idiotype on the immunoglobulin proteins they express on their surface. One of the difficulties in treating these cancers is that each cancer expresses a unique idiotype. Developing a therapeutic treatment that effectively and selectively treats all possible idiotypes has therefore been elusive.
Conventional treatments for hematological cancers typically involve procedures that destroy all blood producing cells in the bone marrow, including the malignant clone, followed by bone marrow replacement with stem cells isolated from the patient or bone marrow from a matched donor to reconstruct the blood producing system. These treatments are highly invasive and marginally curative. One approach involves treatment with monoclonal antibody vaccines that recognize cell surface proteins utilized as “markers” for identification. Therapeutics adopting this approach include Compath-H (Alemtuzumab), HLL2 (Epartuzumab), Hu1D10, and Rituximab, (e.g., U.S. Pat. No. 6,455,043). However, a serious limitation with these monoclonal antibody based therapeutics is that the targeted cell surface antigens are often found on both normal as well as malignant cells. In addition, because of the difficulties in producing human monoclonal antibodies, monoclonal antibody vaccines typically utilize “Chimeric” antibodies, i.e., antibodies which comprise portions from two or more different species (e.g., mouse and human). Repeated injections of such foreign antibodies can lead to the induction of immune responses leading to harmful hypersensitivity reactions. For murine-based monoclonal antibodies, this is often referred to as a Human Anti-Mouse Antibody response (“HAMA” response). Patients may also develop a Human Anti-Chimeric Antibody response (“HACA” response). HAMA and HACA can attack “foreign” antibodies so that they are, in effect, neutralized before they reach their target site(s). A further drawback to monoclonal antibody vaccines is the time and expense required to produce monoclonal antibodies. This is particularly problematic considering that targeted epitopes, such as CD20, CD19, CD52w, and anti-class II HLA can readily mutate to form new tumors that are resistant to previous therapeutics (see e.g., Clinical Cancer Research, 5:611-615, 1999). Thus, there is a need in the art for effective, low cost therapeutics for treating malignancies by selectively targeting an individual's cancerous cells over benign cells.
Like malignant cells, the cells of transplanted tissues and organs display cell-surface epitopes that are differentially expressed in transplanted cells relative to native cells. In some aspects, the present invention is directed to therapeutics that can be targeted to the cells of transplanted tissues or organs by recognition of such variable epitopes. Transplant rejection is caused by an immune response to alloantigens on the transplanted cells, which are proteins specific for an individual patient (including the donor), and which are thus perceived as foreign by the recipient. The most common alloantigens involved in transplant rejections are MHC (major histocompatibility complex) molecules, which are expressed on the surface of transplanted cells and are highly polymorphic among individuals. Foreign MHC molecules are recognized by the recipient's immune system, causing an immune response that leads to rejection of the transplant.
One pathway through which the immune system rejects transplanted tissues is complement-mediated immunity, which can be activated by binding of C1 (a first component of complement) to an immune complex consisting of an MHC antigen on a transplanted cell and the recipient's natural antibody against the MHC antigen. Activation of the pathway results in the assembly of enzymes called C3 convertases, which cleave the complement component C3 to form C3a and C3b. Some of the C3b molecules then bind to the C3 convertases to cleave C5 to C5a and C5b. The biological activities of the complement system, in turn, are derived from the cleavage products of C3 and C5. Another subcomponent of the complement system, C1q, is involved in the initial steps of complement activation. To date, methods for treating transplant rejection by modulating complement-mediated immunity have suffered from side effects associated with non-selectivity, due, for example, to the suppression of all complement-mediated immune responses by a therapeutic agent, which eliminates an important component of the immune system's ability to protect against foreign molecules.
Accordingly, there is a need in the art for effective, low cost therapeutics for reducing or preventing transplant rejection by selectively inhibiting the body's immune response against transplanted cells while retaining protection against foreign pathogens, and/or by selectively destroying particular cell types that stimulate a larger immune response.